Although organisms have immune systems to protect themselves from cancer cells arising from their own bodies, the immune systems often decline in their function and do not work on cancer cells once cancer progresses. Recently, it has been revealed that cancer cells have some functions to evade the immune systems of organisms. One of the functions is that cancer cells produce cytokine such as IL-10 and TGF-β, which induces naive T cells to inducible regulatory T cells (iTregs). Against cancer cells, the cellular immunity in which killer T cells play a central role is important means. Once iTregs which effect on immunosuppression are increased, however, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) which is expressed on the surface of cell membrane reduces the number of killer T cells, which makes impossible to kill cancer cells. CTLA-4 molecule is a member of immunoglobulin superfamily which is expressed on the surface of a regulatory T cell, and inherently CTLA-4 molecule works as a negative feedback control factor when dendritic cells or macrophages provide T cells with an antigen presentation, and controls these cells (Non-Patent Literature 1).
Methods for treating cancer are mainly surgical, chemical, and radiation therapies, but there have not been any established treatment methods which can bring in some sufficient effect yet, thus is desired to establish a novel method for the treatment. The molecule which inhibitively acts on immunity, such as CTLA-4 is referred to as “immune checkpoint”, and CTLA-4 has been a new target for treating cancer as one of the immune checkpoint (Non-Patent Literature 2 and 3). In addition, IL-10 which is produced from various immunocompetent cells also inhibitively acts on immune systems, and it is known that cancer cells also produce IL-10 (Non-Patent Literature 4 and 5). Thus, it is expected that cancer can be treated by inhibiting CTLA-4 expression in regulatory T cells (Tregs) and/or immunosuppressive cytokine IL-10 production, and therefore, compounds which have such function has attracted attention as a novel cancer treatment.
Anti-CTLA-4 antibody (ipilimumab), anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-PD-L1 antibody (MPDL3280A, MEDI4736) have already been developed as inhibitors of immune checkpoint which target CTLA-4 and PD-1 (or PD-L1) so far, but these medicines are antibody drugs and no small molecule as an inhibitor of immune checkpoint has discovered yet.